Efficient ring opening of protected and unprotected aziridines promoted by stable zinc selenolate in ionic liquid

Article abstract of DOI:10.1055/s-0030-1259082

A highly efficient protocol is reported for the synthesis of chiral β-seleno amines via the ring-opening reaction of aziridines. Under neutral conditions, employing a stable phenyl selenolate specie (PhSeZnBr) and (BMIM)BF₄ as solvent, β-seleno

Full text of DOI:10.1055/s-0030-1259082

LETTER
69
Efficient Ring Opening of Protected and Unprotected Aziridines Promoted by
Stable Zinc Selenolate in Ionic Liquid
R
ingOpening
y
of Protected
e
and
U
npro
d
tected
A
ziridine
s
M. Salman,a Ricardo S. Schwab,a Eduardo E. Alberto,a Josimar Vargas,a Luciano Dornelles,*a
Oscar E. D. Rodrigues,*a Antonio L. Braga*b
a
Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
E-mail: rodriguesoed@ymail.com
Departamento de Química, Universidade Federal de Santa Catarina, 88040-970 Florianópolis, SC, Brazil
b
E-mail: albraga@qmc.ufsc.br
Received 1 October 2010
b-seleno amines and selenocysteine derivatives has been
Abstract: A highly efficient protocol is reported for the synthesis
of chiral b-seleno amines via the ring-opening reaction of aziri-
dines. Under neutral conditions, employing a stable phenyl seleno-
late specie (PhSeZnBr) and (BMIM)BF4 as solvent, b-seleno
successful accomplished, most procedures often require
basic or acid reaction conditions and the use of undesir-
able, from an environmental point of view, organic sol-
amines were obtained in good to excellent yields. Reuse of the ionic vents (Scheme 1).15 In this context, we recently reported
liquid was also possible, and four runs were performed with no de-
the synthesis of unsymmetrical diorganyl selenides using
ionic liquid as an efficient and recyclable medium.16 The
crease in the yields.
Key words: chiral b-seleno amines, ring opening reaction, aziri-
dine, ionic liquid
advantages of employing ionic liquids, such as the high
reactivity, their readily commercial availability, ease of
preparation and handling as well the environmental as-
pects, justified our choice to employ them in our work.17
Organoselenium chemistry is a field of continuous inter-
est in modern organic synthesis.1 Organoselenides are
versatile tools in many synthetic transformations, and
have found a broad range of applications as radical pre-
cursors, in elimination and oxidation reactions, and as se-
lenium-stabilized carbanions.2 Moreover, chiral selenide-
and diselenide-containing ligands offer attractive and
practical options in the development of asymmetric trans-
formations.3
R1
R1
R1
R3SeSeR3, NaBH4
THF, EtOH
R3SeSeR3, Zn0
HCl, Et2O
SeR3
SeR3
NHBoc
N
R2
NH2
35–83%
65–90%
R3SeSeR3, InI
CH2Cl2
O
MeO
SeR3
The biological and medicinal properties of selenium and
organoselenium compounds are also increasingly appreci-
ated, mainly due to their antioxidant, antitumor, antimi-
crobial, and antiviral properties.4 In this context, synthetic
methods for the preparation of selenocysteine,5 selenium-
based peptides,6 selenoglycosides,7 selenonucleosides,8
and other important natural coumpounds9 is nowadays an
area of intensive research.
NHBoc
60–98%
Scheme 1 Examples of ring opening of aziridines with R3SeSeR3
using different reducing agents and conditions
In the course of our pursuit of the synthesis and applica-
tion of functionalized organoselenium compounds in or-
ganic synthesis,18 we report herein a new methodology to
prepare b-seleno amines in a neutral and smooth protocol.
Using a bench-stable phenyl selenolate specie (PhSeZn-
Br), recently described by Santi et al.19 to promote the
ring-opening reaction of protected and unprotected aziri-
dines in (BMIM)BF4, the desired products were obtained
in good to excellent yields, in really short time and with
the advantage of recycle the reaction media, which repre-
sents an environmentally benign approach.
The development of new methods for the introduction of
selenium-containing groups into organic molecules, par-
ticularly in a stereocontrolled manner, remains a signifi-
cant challenge. Many reports appeared in the literature
describing the use of selenium as a nucleophilic agent
through the reduction of Se–Se bond, especially cleaveage
of diaryl diselenides. Such procedures commonly em-
ployed NaBH4,10 Zn,11 Zn/In(III),12 and InI13 among oth-
ers.14
Aiming to achieve the optimum conditions, Boc-protected
aziridine 1a was selected as a model substrate. Our studies
started by comparing the feasibility of ionic liquids to pro-
mote the reaction efficiently, compared with the well-
known organic solvents applied for this purpose
(Table 1). We selected (BMIM)BF4, (BMIM)PF6, and
(BMIM)NTf2 to be evaluated. Using THF under reflux,
the product 2a was obtained with higher yield than when
In recent years our group has been working extensively
towards the development of protocols to prepare orga-
noselenium compounds. Although synthesis of chiral
SYNLETT 2011, No. 1, pp 0069–0072
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.12.2010
DOI: 10.1055/s-0030-1259082; Art ID: S07210ST
© Georg Thieme Verlag Stuttgart · New York

70
S. M. Salman et al.
LETTER
the reaction was carried out at room temperature (entries
1 and 2). When CH2Cl2 was used, a decrease in the yield
was observed, affording the corresponding product in
70% yield (entry 3). Acetonitrile, EtOAc, and EtOH were
also used and they were less effective than THF: 67%,
50% and 62%, respectively (entries 4–6). Water was also
used (entry 7), but unfortunately the product was obtained
in a lower yield. By using (BMIM)BF4, (BMIM)PF6, and
(BMIM)NTf2 at 90 °C for 24 hours, the product was
formed in 86%, 26%, and 31% yields, respectively (en-
tries 8–10). With these results in hands, (BMIM)BF4 was
chosen for the subsequent reactions. When the reaction
was conduced at room temperature, a significant decrease
in the yield was found (entry 11). The reaction time was
also evaluated, and it was noted that, when the time was
reduced to 12 hours, 4 hours, and 1 hour (entries 12–14),
the yields were at the same level as those in 24 hours. We
also used PhSeZnCl as nucleophile, however, the product
Table 2 Ring-Opening Reaction of Aziridines 1a–g
R1
R1
PhSeZnBr
SePh
N
R2
1a–g
(BMIM)BF4
90 °C, 1 h
NHR2
2a–g
Entrya
R1
R2
Boc
Boc
Ts
Ts
Ts
H
Product
2a
Yield (%)b
1
2
3
4
5
6
7
Bn
81
60
99
90
85
70
52
i-Pr
Bn
2b
2c
i-Pr
i-Bu
i-Pr
i-Bu
2d
2e
2f
H
2g
was obtained in a lower yield when compared with a Reaction conditions: (BMIM)BF4 (1 mL), PhSeZnBr (0.5 mmol),
and aziridine (0.5 mmol).
PhSeZnBr (entry 15).
With the optimal conditions in hands,20 and in order to
b Isolated yields.
evaluate the scope and limitations of the reaction proce-
dure, the present protocol was extended to a broader range
of protected and unprotected aziridines 1a–g (Table 2).
Table 1 Optimization of the Solvent in the Ring-Opening Reaction
of Aziridine 1a by PhSeZnBr
The N-Boc-protected aziridine 1b, derived from L-valine
gave the product in 60% yield (entry 2). For N-Ts-protect-
ed aziridines 1c–e better yields were obtained, the b-sele-
no amine 2c, derived from L-phenylalanine, was achieved
in quantitative yield (entry 3). Unprotected aziridines 2f
and 2g also underwent the reaction, furnishing the desired
products in goods yields (entries 6 and 7). These aziri-
dines commonly require severe reaction conditions to un-
derwent ring opening (e.g., use of Lewis acid and reflux
for several hours) affording the products in low yield and
with poor regioselectivity.21
Ph
PhSeZnBr
solvent
Ph
SePh
NHBoc
N
Boc
1a
2a
Entrya Solvent
Time (h)
24
24
24
24
24
24
24
24
24
24
24
12
4
Temp (°C) Yield (%)b
1
2
THF
r.t.
65
85
70
67
50
62
42
86
26
31
50
84
82
81
68
THF
reflux
reflux
reflux
reflux
reflux
reflux
90
3
CH2Cl2
MeCN
EtOAc
EtOH
H2O
An important feature of ionic liquids is that they are readi-
ly recyclable, which makes their use an excellent alterna-
tive, mainly considering economic and environmental
aspects.17 Thus, as a further extension to our work, we ver-
ified the possibility to recycle the ionic liquid. The data
shown in Figure 1 illustrate that the medium can be reused
for at least four times without loss of yield in the ring-
opening reaction of aziridine 1c.
4
5
6
7
8
(BMIM)BF4
(BMIM)PF6
(BMIM)NTf2
(BMIM)BF4
(BMIM)BF4
(BMIM)BF4
(BMIM)BF4
(BMIM)BF4
We also extended our protocol to other electrophiles
(Scheme 2) and useful compounds such as seleno ester 322
and diorganyl selenides 4 and 523 were synthesized in
good to excellent yields.
9
90
10
11
12
13
14
15c
90
r.t.
In summary, we have described a practical and concise
synthesis of structurally diverse chiral b-seleno amines
via the ring-opening reaction of protected and unprotected
aziridines. In a straightforward and flexible synthetic
route, using PhSeZnBr as a nucleophile in BMIM(BF4),
which was susceptible for further reuse without loss of ef-
ficiency for at least four runs. Notable features of our ap-
proach are the use of bench-stable phenyl selenolate
specie in neutral conditions, the recycling of the reaction
media and the high reactivity towards unprotected aziri-
dines, making this an efficient and desirable approach. We
90
90
1
90
1
90
a Reaction conditions: solvent, PhSeZnBr (0.5 mmol), and aziridine
(0.5 mmol).
b Isolated yields.
c PhSeZnCl was used as nucleophile instead of (PhSeZnBr).
Synlett 2011, No. 1, 69–72 © Thieme Stuttgart · New York

LETTER
Ring Opening of Protected and Unprotected Aziridines
71
In Organoselenium Chemistry; Wiley: New York, 1987.
(c) Wirth, T. Organoselenium Chemistry – Modern
Developments in Organic Synthesis, In Topics in Current
Chemistry, Vol. 208; Springer: Heidelberg, 2000.
(3) For a comprehensive review about the use of chiral
organoselenium in asymmetric catalysis, see: (a) Wirth, T.
Tetrahedron 1999, 55, 1. (b) Wirth, T. Angew. Chem. Int.
Ed. 2000, 39, 3740. (c) Braga, A. L.; Lüdke, D. S.; Vargas,
F.; Braga, R. C. Synlett 2006, 1453. (d) Braga, A. L.;
Lüdtke, D. S.; Vargas, F. Curr. Org. Chem. 2006, 10, 1921.
(e) Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J.
Org. Chem. 2009, 1649.
(4) (a) Mugesh, G.; Singh, H. Chem. Soc. Rev. 2000, 29, 347.
(b) Mugesh, G.; Du Mont, W. W.; Sies, H. Chem. Rev. 2001,
101, 2125. (c) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T.
Chem. Rev. 2004, 104, 6255. (d) Sarma, B. K.; Mugesh, G.
Org. Biomol. Chem. 2008, 6, 965. (e) Alberto, E. E.;
do Nasciemento, V.; Braga, A. L. J. Braz. Chem. Soc. 2010,
21, 2032.
(5) (a) Phadnis, P. P.; Mugesh, G. Org. Biomol. Chem. 2005, 3,
2476. (b) Schneider, A.; Rodrigues, O. E. D.; Paixão, M. W.;
Appelt, H. R.; BragaA, L.; Wessjohann, L. A. Tetrahedron
Lett. 2006, 47, 1019. (c) Braga, A. L.; Vargas, F.; Galetto,
F. Z.; Paixão, M. W.; Schwab, R. S.; Taube, P. S. Eur. J.
Org. Chem. 2007, 5327. (d) Wessjohann, L. A.; Schneider,
A. Chemistry & Biodiversity 2008, 5, 375; and cited
references.
(6) Braga, A. L.; Lüdtke, D. S.; Paixão, M. W.; Alberto, E. E.;
Stefani, H. A.; Juliano, L. Eur. J. Org. Chem. 2005, 4260.
(7) (a) Mukherjee, C.; Tiwari, P.; Misra, A. K. Tetrahedron Lett.
2006, 47, 441. (b) Tiwari, P.; Misra, A. K. Tetrahedron Lett.
2006, 47, 2345.
Figure 1 Reuse of the reaction media for the ring-opening reaction
of aziridine 1c
O
Br
O
PhSeZnBr
(BMIM)BF4
90 °C, 1 h
SePh
Ph
Cl
Ph
SePh
3 (35%)
4 (94%)
Br
(8) (a) Jeong, L. S.; Tosh, D. K.; Kim, H. O.; Wang, T.; Hou, X.;
Yun, H. S.; KwonY, ; Lee, S. K.; Choi, J.; Zhao, L. X. Org.
Lett. 2008, 10, 209. (b) Braga, A. L.; Filho, W. A. S.;
Schwab, R. S.; Rodrigues, O. E. D.; Dornelles, L.; Braga,
H. C.; Lüdtke, D. S. Tetrahedron Lett. 2009, 50, 3005.
(9) (a) Caputo, R.; Capone, S.; Greca, M. D.; Longobardo, L.;
Pinto, G. Tetrahedron Lett. 2007, 48, 1425. (b) Abdo, M.;
Knapp, S. J. Am. Chem. Soc. 2008, 130, 9234.
SePh
5 (73%)
Scheme 2 Synthesis of selenoester 3 and diorganyl selenides 4 and 5
believe that the chemistry described herein represents a
new route for the synthesis of chiral organoselenium com-
pounds containing nitrogen, among several applications,
these coumpounds are useful chiral ligands in asymmetric
catalysis. Intensive research in this area is in progress in
our laboratory.
(c) Sculaccio, S. A.; Rodrigues, E. M.; Cordeiro, A. T.;
Magalhães, A.; Braga, A. L.; Alberto, E. E.; Thiemann,
O. H. Mol. Biochem. Parasitol. 2008, 162, 165.
(10) (a) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. Tetrahedron
Lett. 1988, 29, 347. (b) Andreadou, I.; Menge, W. M. P. B.;
Commandeur, J. N. M.; Worthington, E. A.; Vermeulen,
N. P. E. J. Med. Chem. 1996, 39, 2040. (c) Goodman, M.
A.; Detty, M. R. Organometallics 2004, 23, 3016.
(11) (a) Bieber, L. W.; Sá, A. C. P. F.; Menezes, P. H.; Gonçalves,
S. M. C. Tetrahedron Lett. 2001, 42, 4597. (b) Andrade,
F. M.; Massa, W.; Peppe, C.; Uhl, W. J. Organomet. Chem.
2005, 690, 1294. (c) Movassagh, B.; Shamsipoor, M. Synlett
2005, 121. (d) Santi, C.; Santoro, S.; Testaferri, L.; Tiecco,
M. Synlett 2008, 1471.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
general procedures and 1H and 13C NMR spectra of all compounds.
Acknowledgment
(12) Braga, A. L.; Schneider, P. H.; Paixão, M. W.; Deobald,
A. M. Tetrahedron Lett. 2006, 47, 7195.
(13) (a) Ranu, B. C.; Mandal, T.; Samanta, S. Org. Lett. 2003, 5,
1439. (b) Ranu, B. C.; Mandal, T. J. Org. Chem. 2004, 69,
5793.
The authors thank CNPq, CAPES and FAPERGS for financial sup-
port. S.M.S. is grateful to TWAS-CNPq, and R.S.S. and E.E.A. to
CAPES and CNPq, for the PhD fellowships.
References and Notes
(14) (a) Ranu, B. C.; Saha, A.; Mandal, T. Tetrahedron 2009, 65,
2072. (b) Yoshimatsu, M.; Sato, T.; Shimizu, H.; Hori, M.;
Kataoka, T. J. Org. Chem. 1994, 59, 1011. (c) Gujadhur,
R. K.; Venkataraman, D. Tetrahedron Lett. 2003, 44, 81.
(d) Comasseto, J. V.; Lang, E. S.; Tercio, J.; Ferreira, B.;
Simonelli, F.; Correia, V. R. J. Organomet. Chem. 1987,
334, 329.
(1) (a) Sharpless, K. B.; Lauer, R. F. J. J. Am. Chem. Soc. 1973,
95, 2697. (b) Nicolaou, K. C.; Petasi, N. A. In Selenium in
Natural Products Synthesis; CIS: Philadelphia / PA, 1984.
(c) Back, T. G. In Organoselenium Chemistry: A Pratical
Approach; Oxford University Press: Oxford, 1999.
(2) (a) Paulmier, C. In Selenium Reagents and Intermediates in
(15) (a) Braga, A. L.; Lüdtke, D. S.; Paixão, M. W.; Rodrigues,
Organic Synthesis; Pergamon: Oxford, 1986. (b) Liotta, D.
Synlett 2011, No. 1, 69–72 © Thieme Stuttgart · New York

72
S. M. Salman et al.
LETTER
O. E. D. Org. Lett. 2003, 5, 2635. (b) Braga, A. L.; Paixão,
M. W.; Marin, G. Synlett 2005, 1675. (c) Braga, A. L.;
Schneider, P. H.; Paixão, M. W.; Deobald, A. M.; Peppe, C.;
Bottega, D. P. J. Org. Chem. 2006, 71, 4305. (d) Braga, A.
L.; Schwab, R. S.; Alberto, E. E.; Salman, S. M.; Vargas, J.;
Azeredo, J. B. Tetrahedron Lett. 2009, 50, 2309.
J. Org. Chem. 2005, 70, 9021. (c) Braga, A. L.; Lüdtke, D.
S.; Alberto, E. E. J. Braz. Chem. Soc. 2006, 17, 11.
(d) Schwab, R. S.; Galetto, F. Z.; Azeredo, J. B.; Braga,
A. L.; Lüdtke, D. S.; Paixão, M. W. Tetrahedron Lett. 2008,
49, 5094. (e) Sharma, A.; Schwab, R. S.; Braga, A. L.;
Barcellos, T.; Paixão, M. W. Tetrahedron Lett. 2008, 49,
5172. (f) Marin, G.; Braga, A. L.; Rosa, A. S.; Galetto, F. Z.;
Burrow, R. A.; Gallardo, H.; Paixão, M. W. Tetrahedron
2009, 65, 4614. (g) Braga, A. L.; Alberto, E. E.; Soares, L.
C.; Rocha, J. B. T.; Sudati, J. H.; Ross, D. H. Org. Biomol.
Chem. 2009, 7, 43. (h) Alberto, E. E.; Soares, L. C.; Sudati,
J. H.; Borges, A. C. A.; Rocha, J. B. T.; Braga, A. L. Eur. J.
Org. Chem. 2009, 4211.
(16) (a) Narayanaperumal, S.; Alberto, E. E.; Andrade, F. M.;
Lenardão, E. J.; Taube, P. S.; Braga, A. L. Org. Biomol.
Chem. 2009, 7, 4647. (b) Singh, D.; Alberto, E. E.;
Rodrigues, O. E. D.; Braga, A. L. Green Chem. 2009, 11,
1521.
(17) (a) Dupont, J.; Souza, R. F.; Suarez, P. A. Z. Chem. Rev.
2002, 102, 3667. (b) Cassol, C. C.; Ebeling, G.; Ferrera, B.;
Dupont, J. Adv. Synth. Catal. 2006, 348, 243. (c) Ranke, J.;
Stolte, S.; Störmann, R.; Arning, J.; Jastorff, B. Chem. Rev.
2007, 107, 2183. (d) Hapiot, P.; Lagrost, C. Chem. Rev.
2008, 108, 2238.
(19) Santi, C.; Santoro, S.; Battistelli, B.; Testaferri, L.; Tiecco,
M. Eur. J. Org. Chem. 2008, 5387.
(20) Detailed procedure in the Supporting Information.
(21) Hu, R. Tetrahedron 2004, 60, 2701.
(18) For selected examples, see: (a) Braga, A. L.; Lüdtke, D. S.;
Alberto, E. E.; Sehnem, J. A. Tetrahedron 2005, 61, 11664.
(b) Braga, A. L.; Sehnem, J. A.; Vargas, F.; Braga, R. C.
(22) Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2007,
129, 14556.
(23) Taniguchi, N. J. Org. Chem. 2007, 72, 1241.
Synlett 2011, No. 1, 69–72 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.